The hypothalamic control of reproductive function is expressed through the receptor-mediated actions of GnRH on the pituitary gonadotroph. GnRH regulates gonadotroph function and LH secretion by binding to high affinity receptors in the plasma membrane. GnRH recpetors appear to be confined to the pituitary and placenta in primates, but are present in gonads, brain, and other sites in the rat. The mechanism of receptor activation in gonadotrophs involves the integrated actions of several intracellular messenger systems. These include phosphoinositide breakdown and mobilization of intracellular calcium, as well as influx of extracellular calcium. In isolated gonadotrophs, GnRH stimulates the hydrolysis of phosphatidylinositol bisphosphate to diacylglycerol and inositol trisphosphate (InsP3). The role of diacylglycerol and activation of protein kinase C in gonadotrophs has been suggested by studies on the translocation of protein kinase C and its regulation by activators (phorbol esters, synthetic diglycerides) and inhibitors (retinal). Also, the generation of IP3 and promotion of calcium mobilization and entry provides a mechanism for the early elevation of (Ca2+)i during GnRH action. GnRH stimulates the production of several higher inositol phosphates (IP3, IP4, IP5) and causes marked elevation of Ins-4-P rather than Ins-I-P as the major product of polyphosphoinositide metabolism. Arachidonic acid (AA) and its lipoxygenated metabolites also mediate GnRH action, and are generated via activation of diacylglycerol lipase as well as phospholipase A2. The actions of AA on LH release are related to its effects on calcium mobilization and activation of an AA-dependent protein kinase in pituitary cytosol. The role of calcium entry in GnRH action is related to the time course of the LH response, which is at first independent of extracellular calcium but is subsequently dependent on calcium influx during the sustained phase of LH release in GnRH-stimulated gonadotrophs.